Genetic hemochromatosis is classified into four subtypes of which only type 1 is of clinical importance in Caucasians. Type 1 is due to an autosomal recessive inborn error of metabolism; the homozygous C282Y mutation of the HFE gene on chromosome 6 accounts for more than 90% of the clinical phenotype in populations of Celtic origin. The mutation leads to an inadequately high intestinal
iron absorption which may finally cause
iron overload in and damage to various organs. Type 2 is the juvenile form of
iron overload which leads to a severe phenotype prior to age 30 with
cardiomyopathy and
hypogonadism. The corresponding mutations are located in the hemojuveline and
hepcidin genes. Typ 3 has mainly been described in Italian families and refers to mutations in
transferrin receptor 2 gene. Histopathologic and clinical consequences of
type 3 hemochromatosis are similar to those seen in type 1. Types 2 and 3 are autosomal recessive traits.
Type 4 hemochromatosis follows an autosomal dominant trait; the corresponding mutation affects the basolateral
iron carrier
ferroportin 1. Diagnosis of
hemochromatosis is based on determinations of serum
ferritin and
transferrin saturation with the latter being more sensitive and specific. In case of a homozygous C282Y gene test, liver biopsy is not required for diagnosis. Liver biopsy is, however, recommended in C282Y homozygotes at
ferritin values > 1,000 ng/ml because of an increased risk for
liver fibrosis. Phlebotomy treatment is the standard care to remove
iron in
genetic hemochromatosis. Patients treated in the early noncirrhotic stage have a normal life expectancy. Thus, future efforts should aim at early diagnosis.
Iron removal also improves the outcome in cirrhotic patients. Liver
carcinoma may develop in cirrhotic patients despite
iron depletion.
Liver cancers without
cirrhosis are so rare that screening is only recommended in cirrhotic patients.